Custirsen Combo Misses OS Goal in Phase III NSCLC Trial

The combination of custirsen (OGX-011) with docetaxel failed to significantly extend overall survival (OS) compared with docetaxel alone as a second-line treatment for patients with non–small cell lung cancer (NSCLC), according to top-line results from the phase III ENSPIRIT study released by the company developing the drug, OncoGenex Pharmaceuticals.

At the time of the interim analysis, the ENSPIRIT trial had randomized 664 patients with stage IV NSCLC to receive second-line treatment with docetaxel alone or in combination with custirsen. The median OS was 9.0 months with the addition of custirsen versus 7.9 months with docetaxel alone (HR, 0.915; P = .178).

Findings from the ENSPIRIT trial join other disappointing results for custirsen, which were reported earlier this year and in 2014. In the phase III SYNERGY trial, reported in 2014, the addition of custirsen to docetaxel and prednisone failed to improve OS compared with chemotherapy/prednisone for men with metastatic castration-resistant prostate cancer (mCRPC). A similar lack of efficacy was seen with the combination of custirsen and cabazitaxel (Jevtana) for men with pretreated mCRPC in the phase III AFFINITY trial, which was recently reported at the 2016 ESMO Annual Meeting.

Across each of these studies, the addition of custirsen resulted in a hazard ratio of 0.90 to 0.95 for OS when compared with chemotherapy. In the AFFINITY trial, median OS was 14.2 months in the custirsen arm compared with 13.4 months for chemotherapy alone (HR, 0.946; 95% CI, 0.796-1.124; P = .529). In the SYNERGY trial, median OS was 23.4 months with the addition of custirsen compared with 22.2 months with docetaxel plus prednisone alone (HR, 0.93; P = .207).

"Following the negative results of previous custirsen trials, an early final analysis of the ENSPIRIT trial was conducted in an effort to conserve capital and extend our cash runway," Scott Cormack, president and CEO of OncoGenex. "OncoGenex is grateful to the patients who participated in the ENSPIRIT trial and their families for their support, as well as our investigators and our employees for their commitment to improving cancer care for those who need it most."

Patients in the ENSPIRIT trial had received one prior line of platinum-based chemotherapy before enrollment. Prior maintenance therapy, when applicable, was allowed, if began at the end of the initial treatment regimen. The study was initiated in 2012, prior to the introduction of checkpoint inhibitors for patients with NSCLC. The target enrollment for the study was 700 participants, and the study was not planned to complete until July 2017.

Custirsen was given as 3 loading doses of 640 mg over 2 hours 5 to 9 days prior to the beginning of chemotherapy. After this, custirsen was given weekly at 640 mg once every 21 days. In both arms, docetaxel was given at 75 mg/m2 on day 1 of each 21-day cycle.

Plans to submit the data for presentation or publication were not described, in a statement from OncoGenex. The findings released from ENSPIRIT were labeled as a final analysis. Outside of OS data, the company noted that adverse events (AEs) in the study were consistent with other studies exploring custirsen with chemotherapy; however, further data were not released.

In the most recently presented data for the drug, from the phase III AFFINITY trial, which enrolled 636 patients with mCRPC following docetaxel, grade ≥3 AEs were experienced by 75.9% of patients in the custirsen arm compared with 66.3% without the agent. Serious AEs occurred in 49.2% of patients treated with custirsen versus 42.3% in the control arm. The most frequently reported serious AEs with the combination were neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia.

“Despite the negative outcome of the trial, the evaluation of custirsen in prostate cancer was conducted on the basis of solid preclinical and clinical evidence supporting anti-tumor activity,” said principal investigator Karim Fizazi, MD, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, when the findings were presented. “I am obviously disappointed with the results but am proud to have been involved in this program, and we will take the learnings of this trial to advance our knowledge of the disease in the hope to further advance care."

At this time, there are no other registered trials exploring custirsen.